tbuckley/cabot-search huggingface dataset:
Development and validation of the Childhood Cancer Survivor Study-Neurocognitive Questionnaire (CCSS-NCQ) Japanese version.
Authors: Miho Kato, Daisuke Yoneoka, Kevin Urayama, Chikako Kiyotani, Kimikazu Matsumoto, Satomi Sato
Journal: Journal of Clinical Oncology (2022)

e22025 Background: The lives of childhood cancer survivors (CCS) may be impacted by symptoms of neurocognitive dysfunction. Decline in executive function, one component of the construct concept of neurocognitive function, may affect the ability to be independent in later life; thus,ssessment and intervention are important. In the United States, the Childhood Cancer Survivor Study-Neurocognitive Questionnaire (CCSS-NCQ) developed by St. Jude Children’s Research Hospital has been widely utilized in clinical practice. It is a self-administered scale for screening daily difficulties regarding organization, emotional regulation, memory, and task efficiency which all fall under the concept of the executive function. To expand the tools for executive function assessment in Japan, we developed the CCSS-NCQ Japanese version and performed a validation study among the adolescent and young adult (AYA)-CCS population. Methods: The Japanese version of the CCSS-NCQ was developed by conducting linguistic validation. Japanese AYA-CCS of all cancer types were recruited and asked to complete this 32-question self-administered questionnaire. Exploratory and confirmatory factor analysis (FA) with the Promax rotation were conducted. Results: In total, 106 participants responded. The mean age of participants was 20.6 ± 5.3 years, and 49.1% were male. The mean age at diagnosis was 8.7 ± 4.8 years; 46.2% of participants were diagnosed with brain tumors, 37.7% with hematological malignancy, and 12.3% with solid tumors. The FA identified the similar four-factor structure of organization, emotional regulation, memory, and task efficiency as the original CCSS-NCQ with factor loading set at 0.4. The Cronbach’s alpha was 0.84 - 0.92. Conclusions: Neurocognitive dysfunction could be a crucial late complication of childhood cancer, and maintaining executive function, in particular, is essential for sustaining the quality of life among CCS. The CCSS-NCQ Japanese version is the first internationally translated CCSS-NCQ. The successful validation in the Japanese population will expand opportunities for future international collaboration to identify race/ethnicity-based disparities, as well as scale enhancement for application to CCS worldwide.
Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress
Authors: Xihui Liu, Suryavathi Viswanadhapalli, Shourya Kumar, Tae-Kyung Lee, Andrew Moore, Shihong Ma, Liping Chen, Michael Hsieh, Mengxing Li, Gangadhara R. Sareddy, Karla Parra, Eliot B. Blatt, Tanner C. Reese, Yuting Zhao, Annabel Chang, Hui Yan, Zhenming Xu, Uday P. Pratap, Zexuan Liu, Carlos M. Roggero, Zhenqiu Tan, Susan T. Weintraub, Yan Peng, Rajeshwar R. Tekmal, Carlos L. Arteaga, Jennifer Lippincott-Schwartz, Ratna K. Vadlamudi, Jung-Mo Ahn, Ganesh V. Raj
Journal: Nature Cancer (2022)

Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. Herein we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. Our study implicates a targeted strategy for solid tumors, including breast, brain, pancreatic and ovarian, whereby small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death.
Enabling circulating cell-free mRNA theranostics from PD-L1, ALK, ROS1, NTRK to transcriptomic profiling.
Authors: Chen-Hsiung Yeh
Journal: Journal of Clinical Oncology (2022)

3033 Background: Circulating cell-free mRNA (cfmRNA) expression can be considered as a compendium of transcripts collected from all organs. It has the capability of integrating functional and genetic information of tissues, highlighting this analyte’s unique potential as a non-invasive biomarker in early detection, therapy selection and patient follow-up of cancer management. Plasma cfmRNA is usually made up of degraded small fragments of smaller than 200 nucleotides, very low concentration, and with different terminal modification, these properties make it difficult to detect. We have developed, validated and automated a cfmRNA clinical testing workflow for simultaneous measurement of PD-L1 expression, ALK, ROS1 and NTRK fusions. This proprietary real-time qPCR-based process is exosome-free, highly sensitive and requires only half milliliter of plasma with 72-hour turnaround. A plasma cfmRNA profiling database covering 750 genes in 9 major cancer pathways was also established with novel cancer type-specific characteristics. Methods: Circulating cfRNA was extracted from 400 uL of plasma and reverse transcribed to cDNA. The cDNA pool then served as the universal source for multi-biomarker tests. All target primer and probe sets were selected based on RNA secondary structures. Plasma PD-L1 expression, ALK, ROS1, NTRK fusions and transcriptomic profiling were performed by Circulogene CLIA/CAP-complied testing platform. Results: Limit of detection (LOD) for PD-L1, ALK/ROS1 and NTRK were 1.0 copy/uL, 17.5 copies/uL and 28 copies/uL, respectively. For scoring of PD-L1 expression, based on Keynote trials, we used the 30th percentile Ct value as cutoff in qPCR which corresponded to IHC ≥ 50% TPS; while the 66th percentile Ct value corresponded to IHC ≥ 1% TPS. PD-L1 cfmRNA was demonstrated to be an excellent surrogate marker of tissue PD-L1 protein for clinical outcomes with immunotherapy. In a global cfmRNA landscape, a functional transcriptomic databank was also established, including differential gene expression, classification, functional clustering and cancer type-specific signatures. Conclusions: Liquid biopsy qPCR tests targeting PD-L1 expression, ALK, ROS1 and NTRK fusions are commercially available and filling the gap of tissue-based assays and NGS. Our groundbreaking cfmRNA work has research, clinical, and diagnostic value, and provides greater dimensionality to the current knowledge of cfmRNA research and makes a significant jump into understanding and devising strategies to tailor cancer Dx and Rx.
A novel RAS inhibitor for pancreatic ductal adenocarcinoma.
Authors: Tariq Arshad
Journal: Journal of Clinical Oncology (2022)

e16263 Background: Pancreatic cancer has a dismal survival rate and no good therapeutic options. Of all types of cancer, it is Pancreatic cancer that is most closely associated with activating mutations in the RAS oncoprotein. Approximately 90% of pancreatic adenocarcinomas carry point mutations activating RAS. Ras directed targeted therapy is the obvious approach to enhancing treatment options for the disease. There is now an FDA approved targeted RAS therapeutic specific to the RAS12C mutant form. However, this particular mutation is uncommon in Pancreatic cancer. Therefore, drugs which act more broadly on RAS are required. There are currently no approved pan-RAS inhibitors. We have developed a small molecule pan-RAS inhibitor which binds directly to all forms of RAS. It acts to block the ability of RAS and to bind and signal through its effectors. It is active in vitro and in vivo against multiple models of pancreatic cancer. Methods: In silico screening of a virtual compound library was performed to identify an initial candidate inhibitor. Iterative rounds of Medicinal Chemistry informed by structural modeling and bioassay in 3D vs 2D growth assays were performed to identify an enhanced activity derivative. Target binding was confirmed by Microscale Thermophoresis and NMR. RAS/RAF complex status was measured by co-immunoprecipitation of the endogenous proteins. Ras signaling was assayed by Western analysis of Phospho-ERK and RAL-GTP pull down assays. In vitro activity was measured using 3D soft agar assays. In vivo activity was measured by ip or po administration against pancreatic tumor cell line xenografts and pdx systems. Results: The current lead, designated RAS-F binds all three main isoforms of RAS at low uM kd and modulates the RAS effector domain in NMR studies. It suppresses RAS signaling pathways in transient assays and suppresses pancreatic tumor cell growth in soft agar with IC50s below 500nM. It suppresses xenograft development of human and mouse RAS driven pancreatic tumor cell lines and reduces the growth of a pancreatic cancer pdx. Conclusions: We have developed a pre-clinical pan-RAS inhibitor that is active in vitro and in vivo against pancreatic cancer models. Funding: NIH 5U01HL127518-03, Kentucky Lung Cancer Research Program (GJC), Qualigen Therapeutics LLC.
A phase II study of anlotinib in the first-line treatment of locally advanced or metastatic soft-tissue sarcoma: Updated results.
Authors: Tao Li, Zhaoming Ye, Yongzhong Wei, Shoufeng Wang, Yunxia Liu, Jia Chen
Journal: Journal of Clinical Oncology (2022)

e23559 Background: Standard treatment for patients with unresectable locally advanced or metastatic soft-tissue sarcoma is chemotherapy based on anthracyclines, while the tolerance of chemotherapy is limited. Anlotinib had demonstrated promising efficacy and favorable tolerance in the first-line treatment of these patients in the previously report ( 2021 ASCO). We updated the latest long-term efficacy and safety data. Methods: This multicenter, open-label, single-arm, phase II clinical trial (NCT03792542) was done at 7 hospitals in China. Patients diagnosed with locally advanced or metastatic soft-tissue sarcoma who had evaluable lesion per Response Evaluation Criteria in Solid Tumors version 1.1 were eligible for inclusion. Additional inclusion criteria were 1) 18-70 years old, 2) ECOG PS 0-2, 3) chemotherapy intolerance judged by investigators, 4) chemotherapy and anti-angiogenesis treatment naïve. All patients received 12mg anlotinib once daily for 14 days every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Safety assessment was done in patients who received at least one dose of anlotinib. Results: 39 patients (24 males and 15 females) were enrolled between April 2019 to October 2021with a median follow-up 13.4 months (IQR 6.55-19.40), and the median age is 58 (range 23-69) years old. Pathological types included liposarcoma (n = 11), fibrosarcoma (n = 8), undifferentiated pleomorphic sarcoma (n = 5), leiomyosarcoma (n = 4), synovial sarcoma (n = 4), malignant peripheral nerve sheath tumor (n = 4), and others (n = 3). At the data cutoff date on December 27, 2021, the median PFS and median overall survival (OS) were 7.1 months [95%CI 5.42-8.77], 24.3 months [95%CI 14.9-33.7], respectively. The PFS at 6 months was 60.0%, and the OS at 12 months was 76.6%. 37 patients were eligible for the evaluation of tumor response.1 achieved confirmed partial response (PR) and the objective response rate (ORR) was 2.7% (1/37). 30 had stale disease (SD) and the disease control rate (DCR) was 83.8% (31/37). The incidence of adverse events of grade 3 was 33.3%, with a higher incidence of hypertension (12.8%), proteinuria (7.7%) and fatigue (5.1%). Conclusions: Anlotinib has shown encouraging anti-tumor activity and well tolerance in the first-line treatment of locally advanced or metastatic soft-tissue sarcoma who were not suitable for chemotherapy. Clinical trial information: NCT03792542.
Updated efficacy and safety results from the phase 2 study of serplulimab, a novel anti-PD-1 antibody, in patients with previously treated unresectable or metastatic microsatellite instability-high or mismatch repair-deficient solid tumors.
Authors: Jin Li, Shukui Qin, Haijun Zhong, Chuan Jin, Lili Chen, Xianglin Yuan, Qingxia Fan, Kehe Chen, Peiguo Cao, Jianjun Xiao, Da Jiang, Tao Zhang, Hongyu Zhang, Xicheng Wang, Wei Wang, Lin Han, Qingyu Wang, Jun Zhu
Journal: Journal of Clinical Oncology (2022)

2592 Background: Serplulimab is a novel humanized monoclonal antibody against PD-1. At ASCO 2021, we have presented the results from the phase 2 serplulimab study (NCT03941574) in patients with unresectable/metastatic microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) solid tumors who have progressed on or been intolerant to standard therapies with a median follow-up of 7.7 months. Here, we report the updated efficacy and safety results together with the results from sensitivity analysis after another 6-month follow-up. Methods: In this single-arm, open-label, multicenter, phase 2 study, patients aged 18–75 years with histologically or cytologically confirmed unresectable or metastatic MSI-H/dMMR solid tumors were enrolled to receive 3 mg/kg of intravenous serplulimab every two weeks for up to two years. The primary endpoint was objective response rate (ORR) assessed by an independent radiological review committee (IRRC) per RECIST v1.1. Secondary endpoints included ORR assessed by the investigators, duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of July 10, 2021, 108 patients had received at least one dose of study treatment and were included in the safety set (SS). Among them, 68 patients with confirmed MSI-H (by local sites or central lab) were included in the main efficacy analysis population (MEAP); 58 patients with confirmed MSI-H (by central lab) and had no major protocol deviations were included in the sensitivity analysis population (SAP). The median follow-up duration was 13.5 months in the MEAP and 14.0 months in the SAP. IRRC-assessed ORR per RECIST v1.1 was 39.7% (95% CI 28.0–52.3; 3 complete response [CR]) in the MEAP and 43.1% (95% CI 30.2–56.8; 2 CR) in the SAP. Investigator-assessed ORRs were 38.2% (95% CI 26.7–50.8; 1 CR) and 41.4% (95% CI 28.6–55.1; 1 CR) in the MEAP and the SAP, respectively. Median DoR, PFS, and OS were not reached; 12-month OS rate was 74.5% (95% CI 62.2–83.3) in the MEAP and 82.4% (95% CI 69.7–90.1) in the SAP. In the SS, 57 (52.8%) patients had grade ≥3 treatment-emergent adverse events, most commonly anemia (9.3%). Thirteen (12.0%) patients had grade ≥3 immune-related adverse events. Three (2.8%) deaths (2 progressive disease and 1 intestinal obstruction) that might be related to serplulimab were reported. Conclusions: The encouraging antitumor activity and the manageable safety profile sustained after a longer duration of follow-up, supporting the further development of serplulimab as a potential tissue-agnostic antitumor treatment. Clinical trial information: NCT03941574.
The landscape of NFE2L2 alteration in Chinese solid tumor patients.
Authors: Xiuying Xian, Chunhai Li, Hong Meng, Lixin Wang, Chuang Liu, Fanfan Meng, Ling Li
Journal: Journal of Clinical Oncology (2022)

e15126 Background: NFE2L2 encodes a transcription factor which is a member of a small family of basic leucine zipper (bZIP) proteins. NFE2L2 variations were detected in many tumors, such as lung cancer, esophageal cancer, renal cell carcinoma and other cancer types. The landscape of NFE2L2 gene in solid tumors of Chinese population has not been descripted. Methods: 3193 normal-paired samples from patients with solid tumors were analyzed using hybridization capture-based next generation sequencing, and alterations including single base substitution, short and long insertion/deletions, copy number variations, gene fusions and rearrangements. Results: NFE2L2 gene was altered in 2.0% (65 of 3193) of all solid tumors. The frequency of NFE2L2 variations was assessed in multiple cancer types, including lung cancer (33/1109), liver cancer (10/206), colorectal cancer (6/391), stomach cancer (3/227), cervical cancer (3/112), esophageal cancer (3/53), and other cancer types. A total of 54 variations of NFE2L2 were found, mainly in exon 2 (26/54), exon 5 (11/54), exon 3 (4/54) and exon 4 (2/54), no variation in exon 1. NFE2L2 D16G, D21H, R34_S40del, V36_E45del, F37_E45del, R42P, L48P, K53Tfs*2, L62P, E67Q and L76_E78delinsQ in exon 2 have not been reported before. In addition, we identified copy number amplifications of NFE2L2 in four patients, including three lung squamous cell carcinomas and one cervical squamous cell carcinoma patients. Furthermore, in our cohort, NFE2L2 mutation carriers also owned other actionable or driver mutation, the most frequent one was TP53 (71%), followed by PIK3CA (34%), MLL2 (28%), CDKN2A (31%), and ATR (25%). Analysis of co-mutation correlation of NFE2L2 showed that NFE2L2 variation was correlated with ATR, ACVR1B, TERC and Sox2 ( p&lt;0.001). TERC and SOX2 were mainly copy number amplification at chromosome 3q36, and there is higher amplification frequency at 3q36 in squamous cell carcinoma. In TCGA cohort, the patients with NFE2L2 variations and 3q36 amplification had a longer median survival than those group without 3q36 amplification (63.59 vs 32.04 months, p = 0.0459). Conclusions: NFE2L2 deleterious mutations are highly diverse and present at low to moderate frequencies across many cancers. Our results revealed the potential targeted therapeutic strategies and prognostic analysis among NFE2L2 population with solid tumors should be considered in further study.
The relationship between circulating tumor DNA with Merkel cell carcinoma tumor burden and detection of recurrence.
Authors: Tomoko Akaike, Naomi So, Daniel S Hippe, Lindsay Gunnell, Coley Doolittle-Amieva, Kristina Lachance, Evan Thomas Hall, Shailender Bhatia, Richa Rathore, Nicole Hook Rattigan, Kathryn Terese Baker, Angel Augusto Rodriguez, Andrew Ecklund, Alexey Aleshin, Paul Nghiem, Lisa C. Zaba
Journal: Journal of Clinical Oncology (2022)

9566 Background: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a recurrence rate of 40%. Early detection of recurrence can improve outcomes, and effective surveillance is crucial for management of patients with MCC. While Merkel cell polyomavirus (MCPyV) oncoprotein serology is useful in surveillance for MCPyV-positive MCC tumors, patients with MCPyV-negative tumors have no available blood biomarkers and require frequent imaging. This prospective, multicenter study assessed whether circulating tumor DNA (ctDNA) can assess disease burden and detect recurrence regardless of virus status. Methods: A total of 328 blood samples were collected from 125 patients at various time points with a median follow-up of 6 months (range: 0-21 months) between April 2020 to January 2022. Whole-exome sequencing was performed on tumor tissue and matched normal blood to identify a set of somatic, clonal single nucleotide variants, which were tracked in subsequent blood (plasma) samples using a personalized and multiplex PCR-NGS based ctDNA assay (Signatera). Clinically evident disease was defined as MCC noted either by physical exam or by imaging, and molecular evidence of disease was defined as a positive ctDNA test. Surveillance phase began once there was no clinically evident or molecular evidence of disease. Results: Among 125 patients, 47 (38%) had clinically evident MCC and all were found to be ctDNA-positive at the first time point (sensitivity: 100%; 95% CI: 91-100%). Of the 47, 24 were newly diagnosed with MCC and had a median primary tumor size of 2.2 cm (range 0.5-8.5 cm) and a median ctDNA value of 26 mean tumor molecules (MTM)/mL (range: 0.08-1470 MTM/mL). Primary tumor diameter and ctDNA value were strongly correlated (Spearman’s r = 0.81, p &lt; 0.001). Of the 125 patients, 73 (58%) patients were assessed in the surveillance setting and had a total of 152 plasma samples available for longitudinal ctDNA testing. Over this period, 7 ctDNA tests were positive while 145 were negative. After a positive test, 5/7 developed a clinically evident recurrence (4 within 60 days). Of the remaining 2 without clinical recurrence, one had &lt; 60 days of follow-up at time of data analysis. The estimated risk of recurrence, accounting for incomplete follow-up, was 57% within 60 days of a positive ctDNA test (n = 7 tests). In contrast, after a negative ctDNA test (n = 145 tests), the risk of recurrence was 0% within 60 days and 3% between 60-90 days. Conclusions: To our knowledge, this is the largest study to explore ctDNA testing in MCC patients. This study demonstrates that ctDNA testing can detect MCC recurrence early and is a promising clinical surveillance tool regardless of tumor viral status.
The role of PRRX1 in esophageal cancer.
Authors: Jinbao Guo
Journal: Journal of Clinical Oncology (2022)

e16046 Background: Recently, paired related homeobox 1 (PRRX1) was identified as a new EMT inducer that induces EMT in solid tumor. Interestingly, the functions of PRRX1 are significantly different, high expression of PRRX1 predicts less metastasis of breast cancer and a better prognosis. However, we observed the opposite relationship in gastric cancer, which was also reported in colorectal cancer and pancreatic cancer. While the function of PRRX1 in oesophageal cancer and whether PRRX1 induces EMT in oesophageal cancer metastasis have not been determined. Methods: One hundred primary oesophageal cancer tissue specimens were collected, immunohistochemical staining was performed to detect the expression of PRRX1. Cell proliferation, the migration and invasion were detected with different PRRX1 expression in oesophageal cancer cells. And the relationship between PRRX1 and Wnt/β-catenin pathway was also explained. Results: Regulation of PRRX1 expression might exert obvious effects on cell proliferation, especially the migration and invasion of oesophageal cancer cells. Moreover, silencing PRRX1 expression using a short hairpin RNA (shRNA) produced the opposite effects. In addition, when PRRX1 was overexpressed, inhibition of the Wnt/β-catenin pathway with XAV939 negated the effect of PRRX1 on EMT, whereas when PRRX1 was downregulated, activation of the Wnt/β-catenin pathway with LiCl impaired the effect on EMT. Conclusions: PRRX1 is expressed at high levels in oesophageal cancer specimens and is closely related to tumour metastasis in patients with oesophageal cancer. Additionally, PRRX1 induces EMT in oesophageal cancer metastasis through activation of Wnt/β-catenin signalling.
NCCN Guidelines Updates: Management of Patients With HER2-Negative Breast Cancer
Authors: William J. Gradishar
Journal: Journal of the National Comprehensive Cancer Network (2022)

Treatment for metastatic HER2-negative breast cancer is becoming increasingly individualized as more of the tumor landscape is described and drugs are developed to target its pathways. Survival can be prolonged by CDK4/6 inhibitors in patients with hormone receptor–positive tumors and by immunotherapy in those with triple-negative disease. In patients with BRCA1/2 mutations, PARP inhibitors delay disease progression. Antibody–drug conjugates are expected to become critical components of the treatment landscape, and targeted drugs are proving to benefit small subsets of patients.